There is a growing body of evidence from pathological, epidemiological and genetic studies that risk factors for vascular disease also enhance risk of Alzheimer disease (AD). However, epidemiological studies usually lack neuroimaging studies and it is unclear whether the apparent association between vascular risk factors and AD is mediated via ischemic injury to the brain, acceleration of the primary Alzheimer neurodegenerative process, or some other process. Some vascular risk factors are more prevalent in African American and Japanese American populations than in Caucasians. We propose to build upon our earlier work by evaluating the association between APOE, genes involved in vascular function, and other indicators of cerebrovascular health including blood pressure and structural brain imaging (MRI) and susceptibility to AD in these ethnic groups. In order to carry out this project successfully, we will ascertain a total sample of 1000 patients (500 Caucasian, 300 African American, 200 Japanese American) who meet NINCDS/ADRDA criteria for probable or definite AD from 11 centers in the U.S., Canada and Germany. Many patients will be identified from our existing family registry. Family history, medical history, and epidemiological information will be obtained from AD probands and their first-degree relatives using standardized questionnaire instruments and established protocols. A cognitive screening test will be administered to and blood samples will be collected from the proband's living sibs, spouses and children over the age of 50 years. DNA, plasma ABeta isoforms and MRI of the brain will be evaluated in probands and sibs. The scientific aims of this project are to: (1) examine recently discovered associations between risk of AD and magnetic resonance imaging (MRI) variables, adjusting for APOE genotype and other known risk factors; (2) examine the association between single nucleotide polymorphisms (SNPs) in 100 genes posited to have a role in vascular function and AD in 1000 sibships using high throughput genotyping technology, and sib-pair linkage and family-based association methodologies; and (3) compare the relative contributions of these SNPs and non-genetic factors including blood pressure, treatment for hypertension, and plasma ABeta on disease and imaging outcomes in Caucasian, African American and Japanese American sibships. Our family-based design is uniquely suited for disentangling complex gene-environment interactions. Our registry will provide DNA resources and baseline data for studies beyond the next funding period. The ultimate goal of this study is to find new targets, genetic and non-genetic, for therapy.